Throughout this application various publications are referred to in square brackets. Full citations for these references may be found at the end of the specification immediately preceding the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
Systemic lupus erythematosus (SLE) is an autoimmune disorder primarily affecting women during their reproductive years. It is characterized by activation of autoreactive B cells with ensuing elevation in serum autoantibody titers. Autoantibodies against nuclear antigens are found in 95% or more of lupus patients; antibodies to doublestranded (ds) DNA are present in approximately 70% of patients. Titers of anti-dsDNA antibodies correlate with disease activity are most common in patients with renal disease and can be isolated from glomeruli of patients with lupus nephritis [1, 2]. Indeed, many anti-dsDNA antibodies cross-react with glomerular antigens. Clinical involvement of the kidneys occurs in 50 to 80% of lupus patients during the course of their disease and renal pathology is found in as many as 90% of patients at autopsy [3].
More recently, it has been demonstrated that lupus patients with anti-DNA or anti-RNP antibodies experience systemic inflammation as well as discrete target organ injury, with increased expression of type I interferon (IFN) inducible genes in peripheral blood mononuclear cells. This appears to result from activation of plasmacytoid dendritic cells (pDCs) and secretion of IFN, mediated in part by nucleic acid-containing immune complexes (IC) that are internalized by activating Fc receptors (FcRs) and subsequently engage toll-like receptors (TLRs) that recognize nucleic acid ligands or even solely by engaging activating FcRs [4, 5].
C1q is a 460 KDa protein formed by 6 homotrimeric subunits containing a N-terminal collagen-like sequence and a C-terminal globular region. It functions in the innate immune response to clear pathogens by activation of the classical complement cascade [6]. Moreover, it contributes to the clearance of IC and apoptotic cells from the circulation, an activity which is important for maintenance of immune tolerance to self antigens [7]. C1q has also been found to inhibit monocyte to DC differentiation and DC activation and therefore may also play a central role in preventing an aberrant adaptive immune response [8, 9]. Although C1q deficiency is a rare phenomenon, it provides the strongest genetic risk for lupus [10]. Several receptors binding C1q have been identified in various cell types including C1qRp (CD93); cC1qR (calreticulin), CR1 and CD35 which bind the collagen region of C1q; gC1qR (multiligand binding receptor) which binds to the globular domain of C1q; and C1qR02 [11]. Engagement of each of these receptors appears to initiate distinct cellular functions; for example, engagement of C1qRp enhances phagocytosis while engagement of C1qR02 triggers a superoxide burst in neutrophils. Most importantly for an understanding of SLE, absence of C1q has been shown to lead to enhanced IFNα production by both human and murine pDCs [12,13].
The present invention addresses the need for improved therapies, based on C1q, to combat autoimmune conditions, including lupus.